Maria Rosa Ortiz

INTRODUCTION Sinusoidal obstruction syndrome (SOS) and early portal hypertension (ePHT) represent significant hepatic vascular complications following preoperative chemotherapy and liver resection for colorectal liver metastases (CRLM). This study aimed to identify predictors of SOS and ePHT and to develop a risk model for preoperative stratification. METHODS A retrospective analysis was conducted in 108 patients undergoing hepatectomy for CRLM after ≥ 4 cycles of neoadjuvant chemotherapy combined with anti-EGFR or anti-VEGF therapy. SOS severity was graded histologically, and ePHT was defined by thrombocytopenia, splenomegaly, varices, or ascites within 3 months postoperatively. Logistic regression models identified predictors of moderate-to-severe SOS (G2–3) and ePHT. Predictive performance was assessed using receiver operating characteristic (ROC) analysis. RESULTS Moderate-to-severe SOS occurred in 24.07% of patients and ePHT in 21.3%. Independent predictors of SOS were anti-VEGF therapy (protective, OR = 0.214; 95% CI 0.075–0.610; p = 0.004) and preoperative portal vein embolization (PVE) or ligation (risk factor, OR = 2.819; 95% CI 1.019–7.796; p = 0.046). The SOS predictive model showed good discrimination (AUC = 0.75). For ePHT, major hepatectomy (OR = 7.78; 95% CI 2.32–25.99; p < 0.001) and the calculated probability of SOS G2–3 (OR = 40.82; 95% CI 2.60–640.53; p = 0.008) were independent predictors (AUC = 0.80; specificity = 84.3%). Neither SOS nor ePHT significantly affected 90-day mortality (8.3%) or overall survival (p > 0.05). CONCLUSIONS Major hepatectomy and chemotherapy-induced sinusoidal injury are key determinants of ePHT after CRLM resection. Anti-VEGF therapy exerts a protective endothelial effect, while PVE increases risk. Despite their incidence, neither SOS nor ePHT compromised survival, suggesting reversibility with optimized perioperative management.

Background: Colorectal cancer (CRC) is a significant global health burden, with liver metastases representing a key prognostic factor. Neoadjuvant chemotherapy (NAC) has improved outcomes in metastatic CRC (mCRC), and tumor regression is commonly assessed using the Rubbia–Brandt classification. The Poultsides classification defines ≥40% fibrosis as an independent prognostic factor, particularly in patients treated with cetuximab (45.71%). However, the predictive value of this threshold remains under debate, warranting further investigation. Methods: This study evaluates the extent of fibrosis (≥40%) induced by NAC plus anti-epidermal growth factor receptor (anti-EGFR) therapy vs. NAC plus anti-vascular endothelial growth factor (anti-VEGF) therapy in mCRC patients. It also examines the prognostic relevance of the Poultsides and Rubbia–Brandt classifications. A total of 108 patients undergoing liver resection for CRC metastases were included. Statistical analyses were performed using SPSS 28.0 version and R software 4.5 version to compare fibrosis rates and survival outcomes. Results: From September 2005 to January 2023, 108 patients were analyzed: 54 received chemotherapy plus anti-EGFR (Cohort 1), and 54 received chemotherapy plus anti-VEGF (Cohort 2). Fibrosis was significantly higher in Cohort 1 (median 40.0%, IQR: 25.4–53.2) than in Cohort 2 (median 20.6%, IQR: 8.07–36.9), p < 0.001. Overall survival was similar between both cohorts (p = 0.96), with a median follow-up of 41.6 months. Conclusions: Anti-EGFR therapy is associated with greater fibrosis than anti-VEGF, despite similar survival outcomes. The Poultsides classification may be a useful prognostic tool for resected liver metastases in mCRC.

BACKGROUND: Colorectal cancer (CRC) is a significant global health burden, with liver metastases representing a key prognostic factor. Neoadjuvant chemotherapy (NAC) has improved outcomes in metastatic CRC (mCRC), and tumor regression is commonly assessed using the Rubbia-Brandt classification. The Poultsides classification defines ≥40% fibrosis as an independent prognostic factor, particularly in patients treated with cetuximab (45.71%). However, the predictive value of this threshold remains under debate, warranting further investigation. METHODS: This study evaluates the extent of fibrosis (≥40%) induced by NAC plus anti-epidermal growth factor receptor (anti-EGFR) therapy versus NAC plus anti-vascular endothelial growth factor (anti-VEGF) therapy in mCRC patients. It also examines the prognostic relevance of the Poultsides and Rubbia-Brandt classifications. A total of 108 patients undergoing liver resection for CRC metastases were included. Statistical analyses were performed using SPSS and R software to compare fibrosis rates and survival outcomes. RESULTS: From September 2005 to January 2023, 108 patients were analyzed: 54 received chemotherapy plus anti-EGFR (Cohort 1) and 54 received chemotherapy plus anti-VEGF (Cohort 2). Fibrosis was significantly higher in Cohort 1 (median 40.0%, IQR: 25.4–53.2) than in Cohort 2 (median 20.6%, IQR: 8.07–36.9), p< 0.001. Overall survival was better in Cohort 2 (p=0.003), with a median follow-up of 41.6 months. CONCLUSIONS: Anti-EGFR therapy is associated with greater fibrosis than anti-VEGF, despite similar survival outcomes. The Poultsides classification may be a useful prognostic tool for resected liver metastases in mCRC.

Individuals with pancreatic-related health conditions usually show lower diversity and different composition of bacterial and viral species between the gut and oral microbiomes compared to healthy individuals. We performed a thorough microbiome analysis, using deep shotgun sequencing of stool and saliva samples obtained from patients with chronic pancreatitis (CP), pancreatic ductal adenocarcinoma (PDAC), and healthy controls (HCs).We observed similar microbiota composition at the species level in both the gut and oral samples in PDAC patients compared to HCs, among which the most distinctive finding was that the abundance of oral-originated Fusobacterium nucleatum species did not differ between the oral and the gut samples. Moreover, comparing PDAC patients with HCs, Klebsiella oxytoca was significantly more abundant in the stool samples of PDAC patients, while Streptococcus spp. showed higher abundance in both the oral and stool samples of PDAC patients. Finally, the most important finding was the distinctive gut phage–bacterial interactome pattern among PDAC patients. CrAssphages, particularly Blohavirus, showed mutual exclusion with K. oxytoca species, while Burzaovirus showed co-occurrence with Enterobacteriaceae spp., which have been shown to be capable of inducing DNA damage in human pancreatic cells ex vivo. The interactome findings warrant further mechanistic studies, as our findings may provide new insights into developing microbiota-based diagnostic and therapeutic methods for pancreatic diseases.

Identifying biomarkers linked to pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP) is crucial for early detection, treatment, and prevention. Methods: Association analyses of 10 serological biomarkers involved in cell signalling (IFN-γ, IL-6, IL-8, IL-10), oxidative stress (superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities, total glutathione (GSH), malondialdehyde (MDA) levels), and intestinal permeability proteins (zonulin, I-FABP2) were conducted across PDAC (n = 12), CP (n = 21) and control subjects (n = 23). A Mendelian randomisation (MR) approach was used to assess causality of the identified significant associations in two large genetic cohorts (FinnGen and UK Biobank). Results: Observational results showed a downregulation of SOD and GPx antioxidant enzyme activities in PDAC and CP patients, respectively, and higher MDA levels in CP patients. Logistic regression models revealed significant associations between CP and SOD activity (OR = 0.21, 95% CI [0.05, 0.89], per SD), GPx activity (OR = 0.28, 95% CI [0.10, 0.79], per SD), and MDA levels (OR = 2.05, 95% CI [1.36, 3.08], per SD). MR analyses, however, did not support causality. Conclusions: These findings would not support oxidative stress-related biomarkers as potential targets for pancreatic diseases prevention. Yet, further research is encouraged to assess their viability as non-invasive tools for early diagnosis, particularly in pre-diagnostic CP populations.

Hypersialylation is a feature of pancreatic ductal adenocarcinoma (PDA) and it has been related to tumor malignancy and immune suppression. In this work, we have evaluated the potential of the sialyltransferase inhibitor, Ac₅3F_axNeu5Ac, to decrease tumor sialoglycans in PDA and to revert its malignant phenotype. Sialoglycans on PDA cells were evaluated by flow cytometry, and the functional impact of Ac₅3F_axNeu5Ac was assessed using E-selectin adhesion, migration, and invasion assays. PDA tumors were generated in syngeneic mice from KC cells and treated with Ac₅3F_axNeu5Ac to evaluate tumor growth, mice survival, and its impact on blocking sialic acid (SA) and on the tumor immune component. Ac₅3F_axNeu5Ac treatment on human PDA cells decreased α2,3-SA and sialyl-Lewis^x, which resulted in a reduction in their E-selectin adhesion, and in their migratory and invasive capabilities. Subcutaneous murine tumors treated with Ac₅3F_axNeu5Ac reduced their volume, their SA expression, and modified their immune component, with an increase in CD8⁺ T-lymphocytes and NK cells. In conclusion, Ac₅3F_axNeu5Ac treatment weakened PDA cells’ malignant phenotype, thereby reducing tumor growth while favoring anti-tumor immune surveillance. Altogether, these results show the positive impact of reducing SA expression by inhibiting cell sialyltransferases and open the way to use sialyltransferase inhibitors to target this dismal disease.

Currently, there are no reliable biomarkers for the diagnosis of pancreatic cancer (PaC). Glycoproteomic approaches that analyze the glycan determinants on specific glycoproteins have proven useful to develop more specific cancer biomarkers than the corresponding protein levels. In PaC, mesothelin (MSLN) is a neo-expressed glycoprotein. MSLN glycosylation has not been described and could be altered in PaC. In this work, we aimed to characterize MSLN glycans from PaC cells and serum samples to assess their potential usefulness as PaC biomarkers. First, we analyzed MSLN glycans from PaC cell lines and then we developed an enzyme-linked lectin assay to measure core fucosylated-MSLN (Cf-MSLN) glycoforms. MSLN glycans from PaC cells were analyzed by glycan sequencing and through Western blotting with lectins. All of the cell lines secreted MSLN, with its three N-glycosylation sites occupied by complex-type N-glycans, which were mainly α2,3-sialylated, core fucosylated and highly branched. The Cf-MSLN glycoforms were quantified on PaC serum samples, and compared with MSLN protein levels. The Cf-MSLN was significantly decreased in PaC patients compared to control sera, while no differences were detected by using MSLN protein levels. In conclusion, Cf-MSLN glycoforms were differently expressed in PaC, which opens the way to further investigate their usefulness as PaC biomarkers.

Introduction: Human papilloma virus (HPV)-related oropharyngeal carcinoma (OPC) can be considered a new subtype of cancer with different clinical characteristics and prognosis than that related to tobacco. Its incidence is increasing worldwide. Its epidemiology has been widely studied in areas such as North America and Northern Europe, but less is known in Southern Europe. Methods: We analyzed the epidemiology of OPC using the database from Girona’s population-based Cancer Registry, in the North-East of Spain, from 1994 to 2018. To analyze differences between neoplasms related to human papillomavirus or not, we determined the immunohistochemical expression of p16 in cases within four time periods: 1997–1999, 2003–2005, 2009–2011, and 2016–2018. Results: Oropharyngeal cancer incidence increased significantly from 2001 to 2018 with an Annual Percentage of Change (APC) of 4.1. OPC p16-positive cases increased with an APC of 11.1. In the most recent period, 2016–2018, 38.5% of OPC cases were p16-positive. European age-standardized incidence rate was 4.18 cases/100.000 inhabitants-year for OPC cancer and 1.58 for those p16-positive. Five-year observed survival was 66.3% for p16-positive OPC and 37.7% for p16-negative. Conclusions: Although with lower burden than in other regions, p16-positive oropharyngeal cancer is increasing in our area and has a better prognosis than p16-negative OPC.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> David S. Moura1, Rafael Ramos2, Antonio Fernandez-Serra3, Teresa Serrano4, Julia Cruz5, Ramiro Alvarez-Alegret6, Rosa Ortiz-Duran7, Luis Vicioso8, Maria Luisa Gomez-Dorronsoro9, Xavier Garcia del Muro10, Javier Martinez-Trufero11, Jordi Rubio-Casadevall12, Isabel Sevilla13, Nuria Lainez14, Antonio Gutierrez15, Cesar Serrano16, Maria Lopez-Alvarez1, Nadia Hindi1, 17, Miguel Taron1, José Antonio López-Guerrero3 and Javier Martin-Broto1, 17 1Institute of Biomedicine of Sevilla (IBiS, HUVR, CSIC, University of Sevilla), Sevilla, Spain 2Pathology Department, Son Espases University Hospital, Palma, Illes Baleares, Spain 3Laboratory of Molecular Biology, Valencian Oncologic Institute, Valencia, Spain 4Pathology Department, Bellvitge University Hospital, IDIBELL, Barcelona, Spain 5Pathology Department, Valencian Oncologic Institute, Valencia, Spain 6Pathology Department, Miguel Servet University Hospital, Zaragoza, Spain 7Pathology Department, Josep Trueta University Hospital, Girona, Spain 8Pathology Department, Virgen de la Victoria University Hospital, Malaga, Spain 9Pathology Department, Hospital Complex of Navarra, Pamplona, Spain 10Medical Oncology Department, Institut Català d'Oncologia, IDIBELL, Universitat de Barcelona, Barcelona, Spain 11Medical Oncology Department, Miguel Servet University Hospital, Zaragoza, Spain 12Medical Oncology Department, Catalan Oncologic Institute, Josep Trueta University Hospital, Girona, Spain 13Medical Oncology Department, Virgen de la Victoria University Hospital, Malaga, Spain 14Medical Oncology Department, Hospital Complex of Navarra, Pamplona, Spain 15Hematology Department, Son Espases University Hospital, Palma, Illes Baleares, Spain 16Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain 17Medical Oncology Department, University Hospital Virgen del Rocio, Sevilla, Spain Correspondence to: Javier Martin-Broto, email: jmartin@mustbesevilla.org José Antonio López-Guerrero, email: jalopez@fivo.org Keywords: KNGL; miRNA221/222 cluster; KIT; DOG1; IGF1R Received: July 27, 2017 Accepted: February 28, 2018 Published: April 03, 2018 ABSTRACT Introduction: There are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients. Methods: KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test. Results: Hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014). Conclusions: We identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors.